Diethyl boronobenzylphosphonates as substrates in Suzuki–Miyaura reaction

Article abstract of DOI:10.1080/10426507.2017.1284845

N-substituted boronobenzylphosphonates were evaluated as substrates in Suzuki–Miyaura coupling catalyzed by tetrakis(triphenylphosphine)palladium(0) and complex of palladium acetate and (2-biphenyl)dicyclohexylphosphine. It was proven that they may be con

Full text of DOI:10.1080/10426507.2017.1284845

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Diethyl boronobenzylphosphonates as substrates
in Suzuki-Miyaura reaction
Agata Rydzewska, Anna Mangold, Weronika Wanat & Paweł Kafarski
To cite this article: Agata Rydzewska, Anna Mangold, Weronika Wanat & Paweł Kafarski (2017):
Diethyl boronobenzylphosphonates as substrates in Suzuki-Miyaura reaction, Phosphorus, Sulfur,
and Silicon and the Related Elements, DOI: 10.1080/10426507.2017.1284845
To link to this article: http://dx.doi.org/10.1080/10426507.2017.1284845
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ACCEPTED MANUSCRIPT
Diethyl boronobenzylphosphonates as substrates in Suzuki-Miyaura reaction
Agata Rydzewska, Anna Mangold, Weronika Wanat and Paweł Kafarski
Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Science and
Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland
CONTACT pawel.kafarski@pwr.edu.pl
This paper is dedicated to the memory of Prof. Harry R. Hudson a pioneer of aminophosphonate
chemistry.
ABSTRACT
N-substituted boronobenzylphosphonates were evaluated as substrates in Suzuki-Miyaura
coupling catalyzed by tetrakis(triphenylphosphine)palladium(0) and complex of palladium
acetate and (2-biphenyl)dicyclohexylphosphine. It was proven that they may be considered as
useful substrates for the preparation of functionalized aminophosphonates.
KEYWORDS
Aminophosphonates, Suzuki-Miyaura coupling, N-substituted (amino)-
boronobenzylphosphonates, C-C bond formation
1
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Introduction
Phosphonic acids are commonly considered as isosteric and isoelectronic analogues of naturally
1
occurring phosphates and as isosteric analogues of carboxylic acids. α-Aminophosphonic acids
occupy an important position among these compounds acting as analogs of amino acids obtained
by substitution of the planar and less bulky carboxylic acid moiety (COOH) by a tetrahedral
2
,3, 4,5
phosphonic acid functionality (PO
3
H
2
).
Phosphonic acid or related group inserted into
peptide chain is known to mimic tetrahedral transition state of hydrolysis of amide bond. This
feature causes that such peptidomimetics quite frequently serve as inhibitors of various
2
,6
proteinases being promising drug candidates against several metabolic disorders. Moreover,
several α-aminoalkylphosphonic acids and derivatives have been isolated from natural sources
7
,8
with most of them displaying antibacterial activity.
The impressive array of applications of aminophosphonic has recently caused that their synthesis
9
,10,11,12,13,14
is a focus of considerable attention and many methods are now available.
Most of the
described methods acids use carbonyl compounds such as aldehydes, ketones, or carboxylic
acids as starting compounds. However, in most cases they give rise to compounds of relatively
simple structures. In order to tailor the structure of aminophosphonic acid to the structural
requirements of certain enzymes or specific cell receptors new procedures leading to more
complex, functionalized aminophosphonic acids are needed. The availability of diethyl (N-
1
5,16
benzylamino)boronobenzylphosphonates
creates such a possibility by application of Suzuki-
Miyaura- reaction. In this paper we describe preliminary studies on the application of this
procedure.
2
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Suzuki-Miyaura reaction (also called Suzuki coupling) relaying on coupling of aryl halides with
organoboronic acids, is one of the most important palladium-catalyzed cross-coupling reactions
of both academic and industrial interest. It conjoins chemically differentiated fragments that
1
7,18,19
participate in electronically divergent processes with palladium catalyst.
Results and Discussion
Suzuki-Miyaura reaction had been only once used previously in aminophosphonate
chemistry in order to enlarge the library of fluorescent aromatic esters of Z-protected
2
0
aminobenzylphosphonic acids.
This paper was devoted to modification of aromatic
phosphonate ester group. In present paper the modification of aminophosphonate side-chain is
proposed.
Diethyl (N-benzylamino)-4-boronobenzylphosphonate 1 and diethyl (N-benzylamino)-3-
2
1
boronobenzylphosphonate 2 were prepared as described earlier through classical addition of
diethyl phosphite to the appropriate Schiff bases obtained from commercially available
formylphenylboronic acids. Diisopropyl (N-benzylamino)-4-boronobenzylphosphonate 3 was
obtained similarly. Corresponding (N-benzylamino)boronobenzylphosphonic acids were
1
5
available from previous studies. However, an effort to use these acids as substrates failed and
no reaction was observed.
Reaction was optimized using compound 1 and p-iodophenol as substrates in the
presence of sodium bicarbonate and palladium catalyst at 80-85C (Scheme 1). Iodophenol was
chosen since the resulting compound 4 may be further functionalized via hydroxyl group. Results
collected in Table 1 indicate that the best results were obtained when using simple
3
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tetrakis(triphenylphosphine)palladium(0) (entry 10). However, the product of this reaction was
accompanied with products of coupling of compound 1 with phenyl moiety of
triphenylphosphine and their separation is cumbesome. Therefore, the popular catalytic complex
of palladium acetate and (2-biphenyl)dicyclohexylphosphine (CyJohnPhos) was used in further
studies. This catalyst applied in dioxane/water solution as 5 molar percent of palladium acetate
and 20 molar percent of CyJohnPhos gave the best results and the yield of the desired product
(
entry 7), although moderate, was satisfactory. It is worth to mention that the reactions carried
out at room temperature and under prolonged reaction time did not give the desired products.
The conditions identical as in those listed in entry 7 were then used to couple iodophenol to
compounds 2 and 3. It resulted in synthesis of aminophosphonates 5 and 6 with similar yield (41
and 46% respectively). The use of a protected form of substrate -- its pinacol ester 7 (Scheme
21
2
), gave unsatisfactory results and the desired product was obtained with 11% of yield.
When trying to obtain diethyl (N-benzylamino)-2-boronobenzylphosphonate quite unexpectedly
2
2
a formation of hydroxyborazaphosphonate 8 was observed. We decided to use this compound
as a substrate for coupling with p-iodophenol. It appeared to be non-satisfactory substrate
because, most likely due to strong steric hindrance, its decomposition was observed (Scheme 3).
When used tetrakis(triphenylphosphine)palladium(0) as catalyst, and despite of the used base
(
sodium bicarbonate or cesium bicarbonate) the results were the same -- production of the
mixture of: (i) diethyl (N-benzyalmino)-2-biphenylmethylphosphonate 9, product of coupling od
compound 8 with phenyl moiety of catalyst; (ii) N-benzylidenebenzylamine 10 and (iii) diethyl
p-hydroxyphenylphosphonate 11, which was formed from diethyl phosphite released from
4
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2
3
compound 8 by Hirao reaction (Scheme 3). These products were isolated with total yield of
6
9% (Scheme 3).
When applied catalytic complex of palladium acetate and (2-biphenyl)dicyclohexylphosphine
only products 10 and 11 were observed with diethyl p-hydroxyphenylphosphonate 11 being the
major one (yield over 50%).
In the second approach diethyl (N-phenylamino)boronobenzylphosphonates 12, 13 and 14 were
coupled with bromobenzene. These substrates were obtained by classical catalyst-free addition of
diethyl phosphite to corresponding Schiff-bases (Scheme 4). Since bromobenzene is less reactive
than
iodobenzene,
tetrakis(triphenylphosphine)palladium(0)
was used (Scheme 4). The
in
mixture
diethyl
of
water/methanol/toluene
expected
(N-
phenylamino)biphenylmethylphosphonates 15, 16 and 17 were obtained in moderate yields
(
(
around 30%) and required purification by column chromatography. Once more application of
N-phenylamino)boronobenzylphosphonic acids failed and no products of coupling were
observed.
Conclusions
Our studies indicate that aminophosphonates functionalized with boronic acid in aromatic parts
of the molecules may be considered as useful substrates for introduction of additional functions
via Suzuki-Miyaura reaction. However, the used of these substrates still requires optimization of
the reaction conditions (especially if considering the catalyst).
5
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Experimental
All solvents and reagents were purchased from commercial suppliers, were of analytical
grade and used without further purification. Unless otherwise specified, solvents were removed
1
31
13
with a rotary evaporator. The H, P and C NMR spectroscopic experiments were performed
1
31
1
on a Bruker Ultrashield Spectrometer operating at 300.13 ( H) MHz, 121.5 MHz ( P{ H}) or a
1
31
1
Bruker Advance II Ultrashied Plus 600.58 MHz ( H), 243.12 MHz ( P{ H}) and 100.61 MHz
1
3
(
C). Measurements were made in CDCl
AG (Dottingen, Switzerland). Chemical shifts are reported in ppm relative to TMS and 85%
PO , used as external standards, while coupling constants are reported in Hz. Mass spectra
3
solutions at 300 K, which was supplied by ARMAR
H
3
4
were recorded at Faculty of Chemistry, Wroclaw University of Science and Technology using a
Waters LCT Premier XE mass spectrometer (method of ionization ESI). The Supplemental
Materials contains sample characterization spectra for compounds 4 and 5 (Figures S 1 -- S 10).
Diethyl (N-benzylamino)-4-hydroxy-p-biphenylmethylphosphonate (4)
Diethyl (N-benzylamino)-4-boronobenzylphosphonate (0.31 g, 0.8 mmol) and sodium carbonate
(
0.17 g, 1.2 mmol) were dissolved in dioxane/water mixture (12/2 mL) and washed by passing
nitrogen gas for 1h. Then iodophenol (0.09 g, 0.41 mmol) and Pd(PPh (24 mg g, 0.025 mmol)
3 4
)
were added and the mixture was refluxed for 7h. After cooling down to room temperature, the
mixture was filtered through celite washing with dioxane (10 mL) and evaporated. The resulting
yellow oil was then dissolved in chloroform (5 mL) and washed successively with: 1M NaOH
solution (5 mL), water (310 mL) and brine (10 mL). Organic phase was dried with magnesium
sulfate, filtered and evaporated. Product was purified by flash chromatography using gradient of
6
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solvent from 100% of hexane to 100% of chloroform. 0.14 g of the desired compound 4 was
obtained as dense white oil (81% of yield).
3
1
1
P NMR (121.5 MHz, CDCl
3
, ppm): δ = 24.06; H NMR (600.58 MHz, CDCl3, ppm): δ = 1.27
1.37 (each: 3H, t, J = 7.1 Hz, OCH CH ), 4.78 (2H, AB system, J = 13.4 Hz, J = 171.8 Hz,
), 3.97-4.01 & 4.06-4.12 (each: 1H, m, OCH ), 4.13 (1H, d, J = 20.6 Hz, CHP), 4.20 (2H,
), 6.68 (2H, d, J = 8.6 Hz, Ar), 7.29-7.38 (7H, m, Ar), 7.44-7.48
4H, m, Ar); C NMR (151.02 MHz, CDCl , ppm): δ = 16.35 & 16.53 (each: d, J = 6 Hz, CH ),
1.14 & 51.25 (each: s, NCH ), 58.97 (d, J = 155.5 Hz, CP), 63.03 & 63.67 (each: d, J = 7.6 Hz,
OCH ), 116.04, 126.67 (d, J = 3.0 Hz), 127.27, 127.84, 128.46 (d, J = 4.5 Hz), 128.96 (d, J = 6
Hz), 131.44, 132.60 (d, J = 4.5 Hz), 139.20, 140.76 (d, J = 3.0 Hz), 159.92; HRMS (TOF MS
&
2
3
NCH
2
2
q-q, JHH = JHP = 7.1 Hz, OCH
2
1
3
(
3
3
5
2
2

+
ESI ): [M+H] Calcd. for C24
H
29NO P: 426.1834 found: 426.1819.
4
Diisopropyl
(N-benzylamino)-4-hydroxy-p-biphenylmethylphosphonate
(5)
--
representative procedure
Diisopropyl (N-benzylamino)-4-boronobenzylphosphonate (0.44g, 1.09 mmol) and sodium
carbonate (0.23 g, 1.6 mmol) were dissolved in dioxane/water mixture (12/2 mL) and washed by
passing nitrogen gas for 1h. Then iodophenol (0.12 g, 0.55 mmol), (2-
biphenyl)dicyclohexylphosphine (40 mg, 0.11 mmol) and Pd(OAc ) (6.1mg, 0.027 mmol) were
2
added and the mixture was refluxed for 7h. After cooling down to room temperature, the mixture
was filtered through celite washing with dioxane (12 mL) and evaporated. The resulting brown
oil was then dissolved in chloroform (5 mL) and washed successively with: 1M NaOH solution
(
5 mL), water (310 mL) and brine (10 mL). Organic phase was dried with magnesium sulfate,
7
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filtered and evaporated. Product was purified by flash chromatography using gradient of solvent
from 100% of hexane to 100% of chloroform. 0.14 g of the desired compound 4 was obtained as
dense white oil (41% of yield).
3
1
1
P NMR (121.5MHz, CDCl
.35 & 1.39 (3H&6H&3H, each: d, J = 6.1 Hz, OCHCH
J = 90.6 Hz, NCH ), 4.05 (1H, d, J = 20.9 Hz, CHP), 4.63& 4.72-4.78 (each: 1H, m, OCH), 6.66
2H, d, J = 8.4 Hz, Ar), 7.29-7.37 (7H, m, Ar), 7.42-7.46 (4H, m, Ar); C NMR (151.02 MHz,
CDCl , ppm): δ = 23.67.35 & 23.94 & 24.20 & 24.22 (each: d, J = 6 Hz, CH ), 51.10 and 51.20
each: s, NCH ), 59.49 (d, J = 157.0 Hz, CP), 63.03 & 63.67 (each: d, J = 7.6 Hz, OCH ),
3
, ppm): δ = 22.17; H NMR (600.58 MHz, CDCl3, ppm): δ = 1.15 &
1
3
), 3.76 (2H, AB system, J = 13.3.6 Hz,
2
1
3
(
3
3
(
2
2
1
1
16.05, 126.52 (d, J = 3 Hz), 127.22, 127.79, 128.46 (d, J = 4.5 Hz), 128.09 (d, J = 6 Hz),
31.44, 132.87 (d, J = 3 Hz), 139.24, 140.60 (d, J = 4.5 Hz), 159.94; HRMS (TOF MS ESI):
+
[
M+H] Calcd. for C26
H
33NO P: 454.5183 found: 454.5184
4
Diethyl (N-benzylamino)-3-hydroxy-p-biphenylmethylphosphonate (6) was obtained as
dense white oil (41% of yield) using identical procedure as described above for compound 6.
3
1
1
P NMR (121.5 MHz, CDCl
3
, ppm): δ = 24.48; H NMR (600.58 MHz, CDCl3, ppm): δ = 1.16
1.37 (each: 3H, t, J = 7.0 Hz, OCH CH ), 3.78 (2H, AB system, J = 13.4 Hz, J = 129.5 Hz,
), 3.82-3.86 & 4.00-4.04 (each: 1H, m, OCH ), 4.13 (1H, d, J = 20.7 Hz, CHP), 4.20 (2H,
), 6.95 (2H, d, J = 8.5 Hz, Ar), 7.27-7.36 (6H, m, Ar), 7.41-7.44 (3H, m, Ar), 7.54 (1H,
&
2
3
NCH
2
2
m, OCH
d, J = 7.6 Hz, Ar), 7.76 (1H, bs, Ar); C NMR (151.02 MHz, CDCl
2
1
3
3
, ppm): δ = 16.21 (d, J = 6
), 51.10 & 51.22 (each: s, NCH ), 59.35 (d, J = 155.5 Hz,
), 115.85, 126.34 (d, J = 6 Hz),
Hz, CH
3
), 16.49 (d, J = 7.6 Hz, CH
3
2
CP), 63.26 (d, J = 7.6 Hz, OCH
2
), 63.72 (d, J = 6 Hz, OCH
2
1
26.53 (d, J = 3 Hz), 127.05 (d, J = 7.6 Hz), 127.24 (d, J = 4.5 Hz), 128.15, 128.43, 128.45,
8
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
+
1
28.78, 131.92, 135.45, 139.14, 141.74 (d, J = 3.0 Hz), 157.02; HRMS (TOF MS ESI ): [M+H]
Calcd. for C24 P: 426.1834 found: 454.1824.
H29NO
4
Diethyl (N-phenylylamino)boronobenzylphosphonates -- general procedure
Appropriate formylboronic acid (0.5 g, 3.35 mmol) was suspended in tetrahydrofurane (30 mL)
followed by addition of aniline (0.31 g, 3.35 mmol). Mixture was stirred for 14 h at room
temperature. Evaporation of the solvent afforded crude Schiff base of satisfactory purity as
yellow oil with 85-95% yield.
Crude Schiff base (0.17 g, 0.84 mmol) was suspended in toluene (40mL0 and diethyl phosphite
was added (102 μL, 0.70 mmol) and the mixture was heated at 85-90C for 10 h. Evaporation of
the solvent provides crude product as brown oil od satisfactory purity. It was not purified but
used directly in the next synthetic step.
Diethyl (N-phenylylamino)-p-boronobenzylphosphonate (12)
3
1
1
Obtained in 63% of yield. P NMR (121.5 MHz MHz, CDCl
400.13 MHz, CDCl3, ppm): δ = 1.12 & 1.26 (each: 3H, t, J = 7.1 Hz, OCH
.68-3.86 (each: 1H, m, OCH ), 3.88-3.92 (2H, m, OCH ), 3.90 (1H, d, J = 21.6 Hz, CHP), 4.74
1H, bs, NH), 6.56 (2H, d, J = 8.6 Hz, Ar), 6.66 (1H, t, J = 7.6 Hz, Ar), 7.04- 7.26 (6H, m, Ar).
3
, ppm): δ = 23.82; H NMR
(
2
CH ), 3.64-3.65 &
3
3
2
2
(
Diethyl (N-phenylylamino)-m-boronobenzylphosphonate (13)
3
1
1
Obtained in 40% of yield. P NMR (121.5 MHz MHz, CDCl
3
, ppm): δ = 24.00; H NMR
CH ), 3.80-3.92 &
), 4.08-4.13 (1H, d, J = 21.8 Hz,
(
300.13 MHz, CDCl3, ppm): δ = 1.14 & 1.26 (each: 3H, t, J = 7.0 Hz, OCH
2
3
3
.96-3.98 (each: 1H, m, OCH
2
), 4.08-3.13 (2H, m, OCH
2
9
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CHP), 4.74 (1H, overlapped with ester peaks of CHP), 6.60-6.71 (3H, m, Ar), 6.99- 7.07 (2H, m,
Ar); 7.24-7.77 (4H, m, Ar).
Diethyl (N-phenylylamino)-o-boronobenzylphosphonate (14)
Obtained in 83% of yield. Efforts to purify this compound by column chromatography were
3
1
unsuccessful because its decomposition. P NMR (121.5 MHz MHz, CDCl
3
, ppm): δ = 24.46;
H NMR (300.13 MHz, CDCl3, ppm): δ = 1.03 & 1.16 (each: 3H, t, J = 7.0 Hz, OCH CH ), 3.30-
.32 (1H, bs, NH), 3.95-4.06 (4H, m, OCH ), 4.88 (1H, d, J = 21.7 Hz, CHP), 6.69-7.58 (9H, m,
Ar)
1
2
3
3
2
Diethyl (N-phenylamino) biphenylmethylphosphonates -- general procedure
Appropriate diethyl (N-phenylamino)boronobenzylphosphonate (0.5 g, 1.63mmol) was
suspended in mixture of metanol (10 mL), saturated sodium dicarbonate solution (10 mL) and
toluene (40 mL). From this mixture oxygen was removed by passing nitrogen gas through for 1h.
Then bromobenzene (0.51g, 3.26 mmol) and Pd(PPh
3
4
) (190 mg g, 0.163 mmol) were added and
the reaction was carried out at 90C under the stream of nitrogen for 6 h. Organic layer was then
separated from aqueous phase, dried under magnesium sulfate and evaporated. The resulting
brown oily product was purified by means of silica-gel column chromatography using mixture of
ethyl acetate and hexane (1:1) as eluent.
Diethyl (N-phenylamino)-p-biphenylmethylphosphonate (15)
3
1
It was obtained as white oil with 32% yield. P NMR (121.5 MHz MHz, CDCl
3
, ppm): δ =
3.25; H NMR (300.13 MHz, CDCl3, ppm): δ = 1.15 & 1.19 (each: 3H, t, J = 7.1 Hz,
OCH CH ), 3.76-3.77 & 3.94-3.99 (each: 1H, m, OCH ), 4.00-4.17 (2H, m, OCH ), 4.85 (1H, d,
1
2
2
3
2
2
10
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J = 20.7 Hz, CHP), 6.62 (2H, d, J = 8.5 Hz, Ar), 6.73 (1H, t, J = 7.6 Hz, Ar), 7.12 (2H, t, J = 7.6

+
Hz, Ar), 7.34 (1H, d, J = 8.5 Hz, Ar), 7.40-7.59 (8H, m, Ar); HRMS (TOF MS ESI ): [M+H]
Calcd. for C23 P: 396.1729 found: 396.1733.
H27NO
3
Diethyl (N-phenylamino)-m-biphenylmethylphosphonate (16)
31
It was obtained as yellowish oil with 29% yield. P NMR (121.5 MHz MHz, CDCl
3
, ppm): δ =
1
2
3.37; H NMR (300.13 MHz, CDCl3, ppm): δ = 1.11 & 1.25 (each: 3H, t, J = 7.1 Hz,
OCH CH ), 3.71-3.74 & 3.95-3.98 (each: 1H, m, OCH ), 4.10-4.17 (2H, m, OCH ), 4.83 (1H, d,
J = 20.9 Hz, CHP), 6.61-6.69 (4H, m, Ar), 7.08-7.11 (2H, m, Ar), 7.43-7.70 (8H, m, Ar); HRMS
2
3
2
2

+
(
TOF MS ESI ): [M+H] Calcd. for C23
H
27NO P: 396.1729 found: 396.1717.
3
Diethyl (N-phenylamino)-o-biphenylmethylphosphonate (17)
3
1
It was obtained as brownish oil with 32% yield. P NMR (121.5 MHz MHz, CDCl
3
, ppm): δ =
4.58; H NMR (300.13 MHz, CDCl3, ppm): δ = 1.07 & 1.24 (each: 3H, t, J = 7.1 Hz,
OCH CH ), 3.74-3.99 (1H, NH), 4.11-4.17 (4H, m, OCH ), 4.96 (1H, d, J = 20.6 Hz, CHP),
.30 (2H, d, J = 8.6 Hz, Ar), 6.63 (1H, t, J = 7.6 Hz, Ar), 7.00 (2H, t, J = 7.6 Hz, Ar), 7.26-7.36
1
2
2
3
2
6

+
(
4H, m Ar), 7.45-7.50 (5H, m, Ar); HRMS (TOF MS ESI ): [M+H] Calcd. for C23
H
27NO P:
3
3
96.1729 found: 396.1722.
Acknowledgements
The work was financed by a statutory activity subsidy from the Polish Ministry of Science and
Higher Education for the Faculty of Chemistry of Wrocław University of Science and
Technology.
11
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Table 1. Coupling of compound 1 with p-iodophenol
Entry
Catalyst (molar
percent)
Solvent
Reaction time (h)
7
Isolated yield
0
1
Pd(OAc)
2
dioxane-water (4:1)
(
(
0.1%)+CyJohnPhos
0.4%)
2
3
4
5
6
7
8
9
Pd(OAc)
2
dioxane-water (4:1)
dioxane-water (4:1
dioxane-water (4:1)
dioxane-water (4:1)
dioxane-water (4:1)
dioxane-water (4:1)
toluene-water (7:1)
dioxane-water (4:1)
7
7
7
7
4
7
2
7
0
(
(
0.5%)+CyJohnPhos
2%)
Pd(OAc)
2
0
(
(
1%)+CyJohnPhos
4%)
Pd(OAc)
2
10
10
31
43
19
46
(
(
2%)+CyJohnPhos
8%)
Pd(OAc)
2
(
(
2%)+CyJohnPhos
8%)
Pd(OAc)
2
(
(
5%)+CyJohnPhos
20%)
Pd(OAc)
2
(
(
5%)+CyJohnPhos
20%)
Pd(OAc)
2
(
(
5%)+CyJohnPhos
20%)
Pd(OAc)
2
(
(
10%)+CyJohnPhos
40%)
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10
Pd(PPh)
4
(5%)
dioxane-water (4:1)
7
81
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Scheme 1. Suzuki coupling of (N-benzylamino)boronobenzylphosphonates with iodophenol
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P(O)(OR)2
N
H
O
B
O
7
Scheme 2. Compound 7 - pinacolate of (N-benzylamino)-4-boronobenzylphosphonate
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P(O)(OEt)2
P(O)(OEt)2
N
Pd(PPh3)4/base
dioxane-water
N
N
H
+
+
HP(O)(OEt)2
B
OH
0
10
25%
8
85-90 C
9
OH
24%
I
HO
P(O)(OEt)2
11
20%
Scheme 3. Decomposition of compound 8 under conditions of Suzuki-Miyaura reaction
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Scheme 4. Suzuki-Miyaura procedure as applied to synthesis of diethyl (N-
phenylamino)biphenylmethylphosphonates
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